Animals whose macrophases have become activated by prior infection or by exposure to bacterial products (lipopolysaccharide or muramyl dipeptide) can survive a challenge infection that is lethal to control animals. The long-term goal of this project is to learn how to regulate the process of macrophage activation so that macrophage microbicidal activity can be stimulated to enhance resistance to infection, and macrophagemediated tissue destruction can be controlled in inflammatory diseases. The following experiments will be undertaken to achieve this goal. To further evaluate the importance of bacterial products in macrophage activation, activation will be studied using human peritoneal macrophages and peritoneal macrophages from germ-free mice. Activation will be evaluated by measuring the macrophages' ability to release microbicidal oxygen radicals when appropriately stimulated. (Macrophages and other phagocytic cells must produce oxygen radicals in order to efficiently kill most pathogenic microorganisms.) Inhibitors of known biochemical regulatory proceses (phosphorylation, methylation, proteolysis, transglutaminase) will be used to determine the mechanism controlling macrophage activation. The regulation of the enzyme responsible for production of oxygen radicals, the NADPH oxidase, will also be examined. The importance of macrophage activation in enhancing microbicidal mechanisms other than those involving oxygen radicals will be evaluated by examing the ability of resident and activated macrophages to kill microorganisms anaerobically. Culture supernatants from a number of intracellular pathogens and a number of periodontal organisms will be tested for ability to block or reverse macrophage activation or to inhibit the NADPH oxidase. Derivatives of muramyl dipeptide, and other drugs selected on the basis of the information gathered above, will be tested for their ability to enhance or inhibit macrophage activation. Such drugs would be valuable clinically in boosting resistance to infection or reducing tissue destruction in periodontal disease and in other inflammatory and infectious diseases.